Chronic kidney disease (CKD) and its progression have a number of detrimental effects on an animal's body. The kidneys play a major role in multiple metabolic and endocrine functions, including controlling red blood cell production from bone marrow. In addition, uremia from progressive renal disease can shorten red blood cell survival.

It is estimated that 32% to 65% of cats with CKD develop anemia as their disease worsens, and that as end-stage kidney disease approaches, almost all of these animals will develop anemia.1-3 Chronic anemia affects the body negatively in a number of ways and decreases an animal's quality of life. Thus, it is important to recognize renal anemia in cats and dogs so the appropriate therapy may be implemented and the treatable causes of anemia corrected.

PATHOPHYSIOLOGY

Anemia is defined as a state of deficient mass of circulating red blood cells and hemoglobin that results in reduced oxygen delivery to the body's tissues and organs and leads to a decrease of the body's metabolic functions. Anemia triggers numerous adaptive response mechanisms because of a lack of adequate oxygen delivery to the tissues, some of which may be detrimental in the long term. In people, for example, chronic anemia leads to an increased heart rate and stroke volume with reduced systemic vascular resistance to maintain adequate tissue oxygenation and may ultimately lead to ventricular hypertrophy.4

Erythrogenesis is mainly controlled by the production of the hematopoietic growth factor erythropoietin in response to anemia.5,6 Erythropoietin is produced primarily in the peritubular interstitial cells of the inner renal cortex and outer medulla in the kidney.5-7 The main stimulus for erythropoietin synthesis is renal hypoxia, which stimulates the erythropoietin gene within the kidneys.8-10 The main site of erythropoietin action is the bone marrow, where it binds to its receptor expressed on the surface of red blood progenitor cells and leads to increased production.7

Table 1: Causes of CKD Anemia

Anemia of renal disease is multifactorial in its pathogenesis (Table 1). As kidney disease progresses, there are fewer erythropoietin-producing cells within the kidneys.6,7,11 Chronic inflammatory disease, commonly present in animals with CKD, also contributes to anemia in patients with kidney disease. Cytokines produced during an inflammatory state help create a relative iron deficiency because of the sequestration of iron within cells of the reticuloendothelial system, making the iron unavailable for red blood cell production.12

Uremia is known to decrease red blood cell survival, but the pathophysiology is unclear and most likely multifactorial.13 Low-grade hemolysis of red blood cells increases as uremia progresses.14 An unidentified uremic toxin is suspected of affecting the red blood cell lifespan.14 In addition, there may be premature clearance of red blood cells by the reticuloendothelial system.15

Uremia causes a platelet dysfunction that can lead to a bleeding diathesis. Many potential reasons contribute to this platelet dysfunction, including the retention of small substances normally eliminated by functioning kidneys that affect platelet function, vascular abnormalities and damage caused by uremia toxins, changes in platelet responsiveness and function, changes in platelet-endothelial interactions, increased concentrations of nitric oxide (a potent platelet antagonist) in uremic states, and dysregulation of the coagulation factors responsible for normal platelet function.16,17

CKD and uremia also predispose animals to gastrointestinal bleeding, with subsequent blood loss; melena is not always clinically evident when chronic low-grade bleeding is present. Gastrin elimination by the kidneys is decreased as renal disease progresses, resulting in increased hydrochloric acid release and hyperacidity in the stomach. Cats with CKD have elevated serum gastrin concentrations.18